Alzheimer's Disease and Gene Discovery on Chromosome 9

描述(申请人提供)：鉴定已与阿尔茨海默病(AD)相关的四个基因[淀粉样前体蛋白、早老素I和2以及载脂蛋白E1]，开辟了新的研究途径，极大地提高了我们对这种常见而复杂的疾病的了解。然而，我们对阿尔茨海默病的遗传基础的了解还远远不完整。近一半的遗传效应还没有得到解释。我们最近完成的协作性阿尔茨海默病项目(CAP)基因组筛查，在迄今为止最大的一组AID家族(455个家系，726个同胞对)中，发现了一个新的基因定位到9p21(MLOD=3.43；在整个数据集中MLS=3.31，MLOD=3.94；在尸检确诊病例子集中MLS=4.41)。初步的随访分析表明，该区域的几个单核苷酸多态(P&lt；0.02)与等位基因相关，进一步加强了我们在9P上存在AD基因的证据。在一项针对与世隔绝的阿拉伯人口的独立研究中，也证实了类似的本地化。 本申请的重点是整合统计学和分子基因组学方法来鉴定9P基因。人类遗传学的惊人进步，包括人类基因组序列草案的完成，以及数百万单核苷酸多态(SNPs)的识别和定位，为我们实现这一目标提供了必要的工具。我们将结合统计和分子方法来鉴定和测试9P上的候选基因，并分离调控AD风险的基因。这将使用多基因家系、不一致的同胞对和病例对照对的互补数据集来完成。我们最初将在所有新获得的家系(-250)中对5个锚定微卫星标记进行基因分型。其次，结合电子技术和实验室发现，我们将识别基因中的SNPs，并确定编码每个候选基因单倍型的最小SNPs集。第三，我们将通过所有三个数据集对每个候选基因的最小SNP集进行高通量基因分型。我们将使用适合每个数据集的统计方法来分析这些数据，以寻找候选基因与AD之间的关联。最后，我们将进行详细的突变和表达分析，以充分表征最有可能的候选基因，并分离出9P AD基因。

DESCRIPTION (provided by applicant): Identifying the four genes [amyloid precursor protein, presenilin I and 2 and apolipoprotein El already associated with Alzheimer disease (AD) has opened new avenues of research and greatly enhanced our understanding of this common and complex disease. Still our understanding of the genetic basis of AD is far from complete. Nearly half of the genetic effect has not been explained. Our recently completed Collaborative Alzheimer Project (CAP) genomic screen, in the largest set of AID families to date (455 families, 726 sibpairs), identified a novel gene localization to 9p21 (MLOD = 3.43; MLS = 3.31 in the overall dataset and MLOD = 3.94; MLS = 4.41 in the subset of autopsy confirmed cases). Preliminary follow-up analyses have demonstrated an allelic association with several single nucleotide polymorphisms in this region (P<0.02), further strengthening our evidence for an AD gene on 9p. A similar localization has been confirmed in an independent study of an isolated Arab population. The present application is a focused effort to integrate statistical and molecular genomic approaches to identify the 9p gene. Breathtaking advances in human genetics, including the completion of the draft human genome sequence and the identification and mapping of millions of single-nucleotide polymorphisms (SNPs), give us the necessary tools to accomplish this goal. We will integrate statistical and molecular methods to identify and test candidate genes on 9p and isolate the gene that modulates the risk of AD. This will be done using complementary datasets of multiplex families, discordant sibpairs, and case-control pairs. We will initially genotype five anchor microsatellite markers in all newly obtained families (-250). Second, using a combination of in silico and laboratory discovery, we will identify SNPs within genes and determine the minimal set of SNPs encoding the haplotypes for each candidate gene. Third, we will perform high throughput genotyping on the minimal SNP set for each candidate gene through all three datasets. We will analyze these data using statistical methods appropriate for each dataset to look for association between a candidate gene and AD. Finally, we will carry out detailed mutation and expression analysis to fully characterize the most likely candidate genes and isolate the 9p AD gene.